PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is an enormous global public health problem and the leading cause of death due to an infectious disease worldwide. A lack of known biomarkers and biologic pathways associated with progression to active TB disease represents a major barrier to the development of point-of-care assays which are urgently needed to effectively diagnose TB at the primary care level, especially in resource-limited countries. With the support of this K23 award, Jeffrey Collins, MD, MPH, MSc, will explore whether high-resolution metabolomics can be used to identify novel metabolic signatures associated with active TB disease and latent TB infection (LTBI) with a high risk of progression to active TB. He will leverage unique clinical cohorts enrolled by the NIAID-funded TB Research Unit (TBRU; U19 AI111211) to determine whether host and Mycobacterium tuberculosis (Mtb) metabolites detected in plasma can be developed as biomarkers of active TB disease (Aim 1), whether changes in host metabolism can identify persons with LTBI at high risk of progression (Aim 2), and whether Mtb-associated metabolites are detectable in the urine of persons with active TB disease (Aim 3). This study seeks to identify novel molecular signatures of active TB and high-risk LTBI with potential for translation into improved diagnostic assays. This research strategy will facilitate a 5-year career development and training plan that will enable Dr. Collins to build on his background in statistical computing and clinical epidemiology and gain critical mentored research training. To achieve independence as a clinical investigator with a unique niche using systems biology to identify novel molecular signatures associated with TB disease and gain new insights into disease pathophysiology, Dr. Collins requires further training in: 1) conducting prospective international clinical research studies; 2) metabolomics and biomarker development; and 3) data science and bioinformatics with a focus on systems biology. To achieve these training aims, Dr. Collins has assembled a multidisciplinary mentorship team that includes lead mentor Dr. Henry Blumberg, an expert in international clinical and translational TB research (and TBRU PI) and co-lead mentor Dr. Dean Jones, an internationally recognized expert in metabolomics. His co-mentors are Dr. Shuzhao Li, an expert in using systems biology to describe the host response to infectious pathogens, Dr. Russell Kempker, an investigator with expertise in evaluation of TB diagnostics, and Dr. Thomas Ziegler, a renowned expert in regulation of host metabolism. Emory University provides an exceptional intellectual and collaborative environment for this research. By leveraging the extensive study infrastructure of the TBRU in Abbis Ababa, Ethiopia and unique expertise in high-resolution metabolomics and systems biology available at Emory University, Dr. Collins will be well positioned to carry out the proposed study aims and training plan and develop the expertise and preliminary data to be competitive for NIH R01 and other funding using multi-omics approaches to better understand and recognize the spectrum of TB disease.